Adrenal Insufficiency inSmith-Lemli-Opitz Syndrome

Hans C. Andersson,1,2* Johnette Frentz,2 Jose E. Martınez,3 Cathy M. Tuck-Muller,3 andJosseline Bellizaire4

1Human Genetics Program, Hayward Genetics Center, Tulane University Medical School, New Orleans, Louisiana2Pediatric Department, Tulane University Medical School, New Orleans, Louisiana3Department of Medical Genetics, University of South Alabama, College of Medicine, Mobile, Alabama4Neonatology Department, Women and Children’s Hospital, Lafayette, Louisiana

We describe three unrelated patients withadrenal insufficiency and RSH or Smith-Lemli-Opitz syndrome (SLOS), a disorderdue to deficient synthesis of cholesterol.These patients presented with hyponatre-mia, hyperkalemia, and decreased aldoste-rone-to-renin ratio, which is a sensitivemeasure of the renin-aldosterone axis. Allpatients had profound serum total choles-terol deficiency (14–31 mg/dl) and markedelevation of 7-dehydrocholesterol (10–45 mg/dl). Two patients were newborn infants with46, XY karyotypes and complete failure tomasculinize; one of these patients also hadcortisol deficiency. Both patients diedwithin 10 days of birth of cardiopulmonarycomplications while on adrenal replace-ment therapy. The third patient diagnosedwith SLOS at birth presented at age7months with fever and diarrhea and wasnoted to have profound hyponatremia. Thispatient is maintaining normal serum elec-trolytes on mineralocorticoid replacement.We conclude that adrenal insufficiency maybe a previously undetected and treatablemanifestation in SLOS. We hypothesize thatdeficiency of cholesterol, an adrenal hor-mone precursor, may lead to insufficientsynthesis of adrenal steroid hormones. Am.J. Med. Genet. 82:382–384, 1999.© 1999 Wiley-Liss, Inc.

KEY WORDS: Smith -Leml i -Opi tz syn-drome; adrenal insufficiency

INTRODUCTION

RSH or Smith-Lemli-Opitz syndrome (SLOS) is arelatively common (1:20,000 live births) autosomal re-cessive disorder comprising facial anomalies, micro-cephaly, limb anomalies, and developmental delay[Smith et al., 1964; Opitz et al., 1994]. Patients fre-quently have ambiguous genitalia and some maleshave had complete failure of masculinization [Greeneet al., 1984; Curry et al., 1987]. The biochemical defectwas recently reported to involve deficient conversion of7-dehydrocholesterol to cholesterol, often resulting inabnormally low serum cholesterol [Tint et al., 1994].

The pathophysiology of cholesterol deficiency inSLOS has not previously been known to affect adrenalhormone synthesis. An early report of a possible abnor-mality in steroid synthesis in SLOS [Chasalow et al.,1985] focused on elevations of DHEA without correla-tion to clinical findings. One report [McKeever andYoung, 1990] suggested a role of fetal adrenal abnor-malities in two cases of SLOS with sex reversal asso-ciated with low maternal estriol levels. Others haveshown a normal hypothalamic-pituitary-gonadal axis[Pankau et al., 1992]. No other endocrine abnormali-ties in SLOS have been described.

We report on three unrelated infants with SLOS whopresented with hyponatremia, hyperkalemia, and ab-normally low aldosterone-renin ratio. These cases offerthe first evidence that cholesterol deficiency in SLOSmay lead to insufficient production of adrenal steroidhormones.

METHODS

Three patients were referred to our institution atbirth for evaluation and treatment of multiple congen-ital anomalies. Analysis of cholesterol and 7-dehydro-cholesterol was performed by Dr. Richard I. Kelley(Kennedy Krieger Institute, Baltimore, Maryland;Cases 1 and 3) or Dr. G. Stephen Tint (Veterans AffairsMedical Center, East Orange, New Jersey; Case 2) andled to the diagnosis of SLOS. All endocrinologic studieswere performed by Endocrine Sciences (CalabasasHills, California). The aldosterone-to-renin ratio, a sen-sitive measure which may detect patients with adrenal

*Correspondence to: Hans C. Andersson, M.D., Human Genet-ics Program, Hayward Genetics Center SL31, Tulane UniversityMedical School, 1430 Tulane Ave., New Orleans, LA 70112. E-mail: handers@tmcpop.tmc.tulane.edu

Received 29 July 1998; Accepted 9 November 1998

American Journal of Medical Genetics 82:382–384 (1999)

© 1999 Wiley-Liss, Inc.

insufficiency with low-normal aldosterone levels, wascalculated from the serum aldosterone and renin levels[McKenna et al., 1992].

RESULTSCase 1

This infant was born at 37 weeks with normal lengthand weight to a 37-year-old G4P3 woman and noted tohave ptosis and anteverted nares, micrognathia, pro-found hypotonia, and ambiguous genitalia. At 3 days,while on parenteral nutrition, serum sodium level wasnoted to be 117 mmol/liter with inappropriately highurine sodium content (Table I). Serum sodium contin-ued to be persistently low despite 4 mEq/kg sodiumchloride per 100 ml added to 1/2 normal saline. Maxi-mum serum potassium value was 5.9 mmol/liter. Stud-ies for adrenal insufficiency were obtained which docu-mented a low serum aldosterone-to-renin ratio andvery low serum cortisol and ACTH (Table I). Florinef0.1 mg/day was begun with slow increase in serum so-dium level. The patient had a 46, XY chromosome con-stitution and an abdominal ultrasound study failed todetect a uterus or gonads. Total testosterone level wasbelow normal (23 ng/dl; normal, 75–400). Serum cho-lesterol was 31 mg/dl (normal, >130) and 7-dehydro-cholesterol was 45 mg/ml (normal, <0.3). The infanthad chronic problems with adequate ventilation. Chestradiographs showed hyperinflation suggesting airwayobstruction and an airway malformation was sus-pected. Echocardiogram was normal. On day 10, thepatient became bradycardic and died of inadequateventilation.

Case 2

This newborn infant was referred on day 3 for man-agement of complex congenital heart disease. At birth,the child was noted to have appropriate weight andlength with microcephaly, micrognathia, bilateral pto-sis, and anteverted nares. Bilateral cataract was pre-sent. The infant was profoundly hypotonic and had fourdigits on the left hand and pulmonic stenosis. The ab-sence of the right kidney with the presence of a rightadrenal was noted. Serum cholesterol was 14 mg/dl and7-dehydrocholesterol was 10 mg/dl. Chromosome con-stitution was 46, XY. The patient had chronic hypona-tremia with an inappropriately elevated urine sodiumconcentration (Table I). Endocrine studies documenteda low aldosterone-to-renin ratio and a normal serumcortisol during acute illness requiring blood pressuresupport due to poor cardiac output. Free testosteronewas low normal (1.8 pg/ml; normal, 1.5–31) The patientdied at 9 days of cardiac insufficiency.

Case 3

This patient was noted at birth to have appropriategrowth parameters and micrognathia, anteverted na-res, misshapen toes, and ambiguous genitalia. Serumcholesterol was 4.1 mg/dl and 7-dehydrocholesterol was10.4 mg/dl, diagnostic of SLOS. Chromosome constitu-tion was 46, XY. Mild hyponatremia (134mmol/liter)was easily corrected. He was treated with 50–150 mg/kg/day oral cholesterol under an experimental protocol(Dr. Richard I. Kelley, Kennedy Krieger Institute). Atage 7 months, he presented with fever, diarrhea, andlethargy for several days. During hospitalization, hy-ponatremia and hyperkalemia were noted with an el-evated urine sodium concentration. Endocrine studiesdocumented an abnormally low aldosterone-to-reninratio and a high normal serum cortisol (Table I).Thepatient was treated with mineralocorticoids with reso-lution of the sodium and potassium abnormalitieswithin 3 days. After 3 months of treatment, he wasmaintaining normal serum electrolytes and was gain-ing weight.

All patients demonstrated hyponatremia and hyper-kalemia with an increased urine sodium concentration.While each patient had aldosterone levels within thelow-normal range, all patients had an abnormally lowaldosterone-to-renin ratio (Table I). Patient 1 had pro-found cortisol deficiency. Cortisol level in Patient 2during a period of extreme stress was in the normalrange, which implies a suboptimal response. Patient 1had an abnormally low total testosterone while Patient2 had a low-normal free testosterone level.

DISCUSSION

In SLOS, mutations in the 7-dehydrocholesterol d7-reductase gene result in cholesterol deficiency and giverise to multiple abnormalities of embryogenesis [Fitzkyet al., 1998; Wassif et al., 1998]. Few data are availableon the pathophysiologic mechanisms causing thesemalformations. Early reports of cholesterol supplemen-tation therapy suggest that some behavioral andgrowth benefits may be seen but the developmentaloutcome is still disappointing [Elias et al., 1997].

While cholesterol is the precursor for the adrenal ste-roid hormones, no clear tendency of SLOS patients todevelop adrenal insufficiency has been reported. Ourthree patients demonstrate relative insufficiency of al-dosterone production, based on aldosterone-to-reninratio, leading to clinically significant electrolyte distur-bances. Patient 1, who did not survive, also had cortisolinsufficiency. Inadequate growth, which is common inSLOS, may, in part, be due to subtle aldosterone orcortisol deficiency that may be overlooked unless adre-nal hormones are quantitated carefully. Adrenal hor-

TABLE I. Serum Aldosterone, Renin, and Sodium Values in Three SLOS Patients

Patient AgeSerum

Na (mmol/L)Urine

Na (mmol/L)Aldosterone

(pmol/L)Renin

(ng/ml/hr)Aldosterone:renin

ratio

1 2 Days 129 102 242 (normal 4 2639, 139–4861) 56 (normal 4 12, 2–35) 4.3 (normal 28–920)2 4 Days 133 41 183 7.8 233 7 Months 129 102 883 (normal 4 861, 139–2500) 148 6.2

Adrenal Insufficiency in SLOS 383

mone therapy may improve growth in such patients.The growth benefit and pubertal progression whichcholesterol supplementation confers on SLOS patientsmay, at least partially, be mediated by improved adre-nal hormone synthesis [Elias et al., 1997].

A relationship has been hypothesized between thefailure of some SLOS patients to develop normallymasculinized genitalia and a deficiency of sex hor-mones [Greene et al., 1984]. Data for this associationhave been lacking and neonatal hormone levels maynot reflect accurately these levels in the early develop-ing embryo when androgen levels, in part, determinesexual development. Nevertheless, one patient withcomplete failure to masculinize had an abnormally lowtotal testosterone (Patient 1) and another had a freetestosterone level in the low-normal range (Patient 2).These findings suggest that there may be an associa-tion between cholesterol deficiency and inadequate sexhormone production.

In summary, we suggest that SLOS patients mayhave insufficient adrenal hormone production. Electro-lyte concentrations in SLOS patients should be mea-sured at birth and monitored during periods of illness.Appropriate adrenal hormone studies should be under-taken in those with electrolyte disturbances.

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TABLE II. Serum Testosterone, Cortisol, ACTH, 17-OH Progesterone and 17-OH Pregnenolone Values in Three SLOS Patients

Patient AgeFree testosterone

(pg/ml)Total testosterone

(ng/dl)Cortisol(mg/ml)

ACTH(pg/ml)

17-OH Progesterone(ng/dl)

17-OH Pregnenolone(ng/dl)

1 2 Days NAa 23 (normal 75–400) 1.0 (normal 2–11) <10 (normal 10–60) 52 (normal 7–77) NA2 4 Days 1.8 (normal 1.5–31) NA 12 57 NA <10 (normal 36–763)3 7 Months NA 76 (normal <30) 17 (normal 6–23) NA 150 196 (normal 42–540)

aNot available.

384 Andersson et al.